Fri Dec 09 2022

90 articles - From Friday Dec 02 2022 to Friday Dec 09 2022

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Guidelines

Guidelines and related publications, position statements, white papers, technical reviews, consensus statements, etc…

Leukemia

A comparison of the International Consensus and 5th World Health Organization classifications of mature B-cell lymphomas.

In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, with focus on mature B-cell neoplasms. The main aim is to provide a tool to facilitate the work of pathologists, hematologists and researchers involved in the diagnosis and treatment of lymphomas.

Pubmed   Journal   ReadQx 


Meta-analysis

meta-analyses and systematic reviews

Haematologica

Investigational venetoclax combination therapy in acute myeloid leukemia - a systematic review and meta-analysis.

Pubmed   Journal   ReadQx 


Original articles

RCT, clinical trials, retrospective studies, etc…

Blood

Activation of the PP2A-B56a heterocomplex synergizes with venetoclax therapies in AML through BCL2 and MCL1 modulation.

Finally, PP2A targeting increases the efficacy of the clinically approved venetoclax and azacitidine combination in vitro, in primary cells, and in an AML patient-derived xenograft model. These preclinical results provide a scientific rationale for testing PP2A-activating drugs with venetoclax combinations in AML.

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DDX41-associated susceptibility to myeloid neoplasms.

Several aspects of deleterious germline DDX41 alleles are noteworthy: (i) Certain variants are common in particular populations; (ii) MNs develop at older ages typical of de novo disease, challenging the paradigm that inherited cancer risk always causes disease in young people; (iii) Despite equal frequencies of these variants in men and women, men progress to MNs more frequently, suggesting a gender-specific effect on myeloid leukemogenesis; and (iv) Individuals with deleterious germline DDX41 variants develop acute severe graft versus host disease after allogeneic hematopoietic cell transplantation with wild-type donors more than others unless they receive post-transplant cyclophosphamide, suggesting a pro-inflammatory milieu that stimulates donor-derived T-cells. Biochemical studies and animal models have identified DDX41's ability to interact with double stranded DNA and RNA:DNA hybrids with roles in mRNA splicing, rRNAs/snoRNAs processing, and modulation of innate immunity, disruption of which could promote inflammation and drive tumorigenesis.

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HLA-E-Restricted Immune Responses Are Crucial for the Control of EBV Infections and the Prevention of PTLD.

The further progression to EBV+PTLD was highly associated with the presence of both peptide-encoding EBV-strains and the expression of HLA-E*0103/0103 in the host. Thus, HLA-E-restricted immune responses and the NKG2A/LMP-1/HLA-E axis are novel predictive markers for EBV+PTLD in transplant recipients and should be considered for future EBV vaccine design.

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S100A9 up-regulated by IFNGR signaling blockade functions as a novel GvHD suppressor without compromising GvL in mice.

Consistent with S100a9-overexpressing T cells in our allo-HSCT model, ahGR-Nab also reduces human T cell trafficking to GvHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GvHD suppressor without compromising GvL.

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The Spectrum of GATA2 Deficiency Syndrome.

Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency including: 1) why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2, 2) what are the genetic changes that lead to myeloid progression, 3) what causes the apparent genetic anticipation, and 4) what is the role of preemptive HSCT.

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Blood Adv

Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells.

Our results show that CAT CAR T-cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared to FMC63 CAR T-cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T-cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B-cells present in the manufacture.

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An NFIX-mediated regulatory network governs the balance of hematopoietic stem and progenitor cells during hematopoiesis.

Additionally, we provide evidence suggesting the absence of NFIX negatively affects PU.1 binding at some genomic loci. Our data support a model in which NFIX collaborates with PU.1 at super-enhancers to promote the differentiation and homeostatic balance of hematopoietic progenitors.

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Anti-FVIII antibodies in Black and White hemophilia A subjects: do F8 haplotypes play a role?

Interestingly, the BDD-FVIII proteins were markedly more reactive than the full-length FVIII products with plasma antibodies. The stronger immunoreactivity of BDD-FVIII suggests that B-domain removal may expose novel B-cell epitopes, perhaps through conformational rearrangements of FVIII domains.

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CD14+/CD31+ Monocytes Expanded by UM171 Correct Hemophilia A in Zebrafish upon Lentiviral Gene Transfer of Factor VIII.

Finally, the HA zebrafish model showed that f8 RNA is predominantly localized in the hematopoietic system at the larval stage, which indicates a potential contributory role of FVIII in hematopoiesis that warrants further investigation. We believe that our study may be of broad interest to hematologists and researchers striving to advance knowledge and permanent treatments for patients with HA.

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Compromised antigen binding and signaling interfere with bispecific CD19 and CD79a chimeric antigen receptor function.

Our study showed that despite added specificity, tandem and bicistronic CAR-T cells exhibit different defects that impair recognition of tumor cells expressing a single antigen. Our data provide support for targeting multiple B cell antigens to improve efficacy and identify areas for improvement of bispecific receptor designs.

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Cord blood transplantation for nonmalignant disorders: early functional immunity and high survival.

We conclude that in the absence of a MRD, UCBT following myeloablative conditioning without serotherapy is an excellent curative option in young children with non-malignant disorders. This trial is registered at as NCT00950846.

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Generation of a humanized afucosylated BAFF-R antibody with broad activity against human B-cell malignancies.

Finally, the tissue specificity of this humanized mAb was confirmed against a broad panel of normal human tissues. Taken together, we have identified a robust lead candidate BAFF-R mAb for clinical development.

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Incidence, Risk Factors, and Impact of Early Cardiac Toxicity after Allogeneic Hematopoietic Cell Transplantation.

ECE was associated with higher NRM (HR 4.68, P<0.001) and lower OS (HR 3.03, P<0.001). Considering that PTCY and TBI were predictors for ECE, and the impact of this complication on transplant mortality, the implementation of cardiac monitoring plans could be appropriate in patients receiving these medications.

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JAK/STAT blockade reverses the malignant phenotype of Hodgkin and Reed-Sternberg cells.

Additionally, longitudinal gene expression analyses provided further mechanistic information about pertinent biological pathways involved, including 37 gene pathways distributed in three main clusters: one was characterized by upregulation of the G2/M checkpoint and MHC-related clusters; two additional clusters showed a progressive down regulation of the tumor-promoting inflammation signatures: JAK/STAT and IL1/IL4/IL13/IL17. Together, our results confirm the therapeutic potential of JAK/STAT inhibitors in cHL, identify CSF3R as a new biomarker, and provide supporting genetic data and mechanistic understanding.

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Minimizing Acute Toxicity and Late Effects in the Treatment of Hodgkin Lymphoma in Patients with Sickle Cell Disease.

A variety of risk-adapted treatment regimens exist that prioritize disease presentation, but not patient-specific comorbidities. Herein we describe a patient with sickle cell disease diagnosed with HL and the considerations made in treatment planning to minimize therapy-related acute toxicity and late effects that overlap with the patient's preexisting sickle cell disease complications.

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Paired bone marrow and peripheral blood samples demonstrate lack of widespread dissemination of some CH clones.

Importantly, we illustrate that CH, including clones with variant allele frequencies >10%, can be confined to specific bone marrow spaces and may be eliminated through surgical excision. Future work will define whether clones with somatic mutations in particular genes or clonal fractions of certain sizes are more likely to be localized or are slower to disseminate into the peripheral blood and other bony sites.

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Predictors of Survival in Patients with MALT Lymphoma: a retrospective, case-control study.

Younger patients had better OS but worse RS. Disease dissemination was the lymphoma-specific risk factor.

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Retained functional normal and preleukemic HSCs at diagnosis are associated to good prognosis in DNMT3Amut NPM1mut AMLs.

Furthermore, we show that while CD34+ subpopulations can contain next to LSCs also normal and/or pre-leukemic Hematopoietic Stem Cells (HSCs), this is not the case in CD34-GPR56+NKG2DL- enriched LSCs which thus can be isolated with high purity. Finally, we show that AML patients, who retain at time of diagnosis a reserve of normal and/or preleukemic HSCs in their bone marrow able to reconstitute immunocompromised mice, have significant longer relapse-free and overall survival compared to AML patients in whom functional HSCs are no longer detectable.

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S1P has a negative effect on RBC storage quality.

All these phenomena were reversed in Sphk1 KO mice or with hypoxic storage. S1P is a positive regulator of energy metabolism and a negative regulator of antioxidant metabolism in stored RBCs, resulting in lower post transfusion recoveries in murine models.

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Salvage therapy with brentuximab-vedotin and bendamustine for patients with R/R PTCL: a retrospective study from the LYSA.

BBv is highly active in patients with R/R PTCL and should be considered as a one of the best option of immunochemotherapy salvage combination in this setting and particularly as a bridge to allogeneic transplant for eligible patients.

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Selected memory T cells infused post haploidentical hematopoietic stem cell transplantation persist and hyper-expand.

Deep immunophenotyping revealed strong polyfunctional effector CMV-specific T cell responses in the majority of patients, with their expansion correlating with the frequency of CMV-specific cells in the donor. These findings provide a rationale behind the suggested improved protection against viral infections for patients receiving CD45RA-depleted DLI.

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Shared graft-vs-leukemia minor histocompatibility antigens in DISCOVeRY-BMT.

We confirmed immunogenicity of an example novel mHA via T cell coculture with peptide-pulsed dendritic cells. This work demonstrates that identification of shared mHAs is a feasible and promising technique for expanding mHA-targeting immunotherapeutics.

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Targeting RARA Overexpression with Tamibarotene, a Potent and Selective RARa Agonist, is a Novel Approach in AML.

These results support further evaluation of tamibarotene-based treatment strategies in AML and MDS patients with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial is registered at as NCT02807558.

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Thrombin mediated activation of PAR1 enhances doxorubicin induced cardiac injury in mice.

In addition, mice with PAR1 deleted in either cardiomyocytes or cardiac fibroblasts demonstrated reduced cardiac injury compared to controls. Taken together, these data suggest that thrombin-mediated activation of PAR1 contributes to doxorubicin induced cardiac injury.

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Blood Cancer J

Second- and third-line treatment strategies in multiple myeloma: a referral-center experience.

Over the last two decades, more patients were treated with newer agents and triplets for relapsed MM. The landscape of regimens has become more diverse, and survival after the first relapse is continually improving.

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Haematologica

DUSP22 rearranged ALK-negative ALCL is a pathogenetically distinct disease but can have variable clinical outcome.

Not available.

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DUSP22 rearrangement is associated with distinctive immunophenotype but not outcome in patients with systemic ALK-negative anaplastic large cell lymphoma.

However, in this cohort DUSP22-R was not associated with a better clinical outcome. Therefore, we suggest that current treatment guidelines for this subset of ALK-negative ALCL patients should not be modified at this time.

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Adipocytes control haematopoiesis and inflammation through CD40 signaling.

In conclusion, adipocyte CD40 plays an important role in maintaining immune cell homeostasis in BM during ageing and chronic inflammatory diseases, particularly of the lymphoid populations. Although adipocyte CD40-deficiency reduces atherosclerosis burden and ameliorates diet-induced obesity, the accompanying T-cell activation may eventually aggravate cardiometabolic diseases.

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ALK-negative anaplastic large cell lymphoma with DUSP22 rearrangement has distinctive disease characteristics with better progression-free survival: a LYSA study.

There were 47/104 (45%) DUSP22-R and 2/93 (2%) TP63-R cases, including one DUSP22-R/TP63-R. DUSP22-R tumors showed more frequent CD3 expression (62% versus 35%, P=0.01), and less commonly a cytotoxic phenotype (27% versus 82%; P.

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Cellular and metabolic characteristics of pre-leukemic hematopoietic progenitors with GATA2 haploinsuficiency.

As oncogenic mutations often accumulate with age, Gata2 deficiency mediated priming of hematopoietic cells for oncogenic transformation may explain the earlier occurrence of MDS/AML in patients with GATA2 germline mutation. The mitochondrial phenotype is a potential therapeutic opportunity for prevention of leukemic transformation in these patients.

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CMV-specific T-cells following haploidentical transplants: reshaping a repertoire by half.

Not available.

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Immune thrombotic thrombocytopenic purpura plasmas induce calcium- and IgG-dependent endothelial activation: correlations with disease severity.

Furthermore, two anti-ADAMTS13 monoclonal antibodies purified from iTTP patient B cells, but not serum from hereditary TTP, induced endothelial Ca2+ flux associated with Weibel-Palade bodies exocytosis in vitro, whereas inhibition of endothelial ADAMTS13 expression using small interference RNA, significantly decreased the stimulating effects of iTTP IgG. In conclusion, Ca2+-mediated endothelial cell activation constitutes a second "hit" of iTTP, is correlated with the severity of the disease and may constitute a possible therapeutic target.

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Measurable residual disease in acute lymphoblastic leukemia: methods and clinical context in adult patients.

However, new approaches to target MRD in patients with T-ALL remain an unmet need. As our MRD detection assays become more sensitive and expanding novel therapeutics enter clinical development, the future of ALL therapy will increasingly utilize MRD as a criterion to either intensify or modify therapy to prevent relapse or de-escalate therapy to reduce treatment-related morbidity and mortality.

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Methotrexate cytarabine thiotepa rituximab (MATRix) chemoimmunotherapy for primary central nervous system lymphoma: a Toronto experience.

Not available.

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Second hematopoietic stem cell transplantation as salvage therapy for relapsed acute myeloid leukemia/ myelodysplastic syndromes after a first transplantation.

Multivariate-analysis identified female gender (HR 0.31, P=0.001), short remission duration after HSCT1 (HR 2.31, P=0.05), acute GVHD after HSCT1 (HR 2.27, P=0.035), HSCT2 from haplo-identical (HR 13.4, P=0.001) or matched-unrelated donor (HR 4.53, P=0.007) and relapse after HSCT1 in earlier years (HR 2.46, P=0.02) as factors predicting OS after HSCT2. Multivariate-analysis of al patients including HSCT2 entered as time-dependent variable identified relapse within 6 months after HSCT1 (HR 2.32, P.

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Sirolimus as frontline therapy for PTEN-mutated histiocytic sarcoma.

Not available.

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Targeting cytokine-induced leukemic stem cell persistence in chronic myeloid leukemia by IKK2-inhibition.

Not available.

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Targetting glutaminase to starve lymphoma cells.

Not available.

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What about (MG)US? Towards tailored testing in monoclonal gammopathies.

Not available.

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J Hematol Oncol

Electrostatic anti-CD33-antibody-protamine nanocarriers as platform for a targeted treatment of acute myeloid leukemia.

We report important results toward innovative personalized, targeted treatment options via electrostatic nanocarrier therapy in AML.

Pubmed   Journal   ReadQx   PMC

Lancet Haematol

25 mm Hg versus 35 mm Hg elastic compression stockings to prevent post-thrombotic syndrome after deep vein thrombosis (CELEST): a randomised, double-blind, non-inferiority trial.

Larger more powerful studies are needed. Funding Laboratoires Innothera, France.

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Leukemia

Analysis and therapeutic targeting of the EP300 and CREBBP acetyltransferases in anaplastic large cell lymphoma and Hodgkin lymphoma.

Importantly, EP300/CREBBP HAT inhibitor A-485 and bromodomain inhibitor CPI-637 exhibited strong activities against ALCL and HL in vitro and in xenograft mouse models, and inhibited PD-L1 mediated tumor immune escape. Thus, our studies revealed critical insights into the physiological roles of EP300/CREBBP in these lymphomas, and provided opportunities for developing novel strategies for both targeted and immune therapies.

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CALR-mutated cells are vulnerable to combined inhibition of the proteasome and the endoplasmic reticulum stress response.

In serial transplantation assays following combined proteasome/IRE1 inhibition for six weeks, we did not find preferential depletion of Calr-mutant long-term HSCs. Together, these findings leverage altered proteostasis in Calr-mutant MPN to identify combinatorial dependencies that may be targeted for therapeutic benefit and suggest that eradicating disease-propagating Calr-mutant LT-HSCs may require more sustained treatment.

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Continuous Indexing of Fibrosis (CIF): improving the assessment and classification of MPN patients.

CIF also shows promise in the identification of MPN patients at risk of disease progression; analysis of samples from 35 patients diagnosed with ET and enrolled in the Primary Thrombocythemia-1 trial identified features predictive of post-ET myelofibrosis (area under the curve = 0.77). In addition to these clinical applications, automated analysis of fibrosis has clear potential to further refine disease classification boundaries and inform future studies of the micro-environmental factors driving disease initiation and progression in MPN and other stem cell disorders.

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Transient regulation of RNA methylation in human hematopoietic stem cells promotes their homing and engraftment.

We show that transient downregulation of YTHDF2 or activation of FTO by using these compounds inhibits CXCR4 decay in CB HSCs and promotes their homing and engraftment. Our results demonstrate a novel regulation strategy to enhance the function of CB HSCs and provide a translational approach to enhance the clinical efficacy of HCT.

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Thromb Haemost

CircRNA circCOL1A1 Acts as a Sponge of miR-30a-5p to Promote Vascular Smooth Cell Phenotype Switch through Regulation of Smad1 Expression.

Upregulation of circCOL1A1 ameliorates the inhibitory effect of miR-30a-5p on its target SMAD1, which leads to suppression of transforming growth factor-ß (TGF-ß) signaling. Our findings demonstrate that circCOL1A1 promotes the phenotype switch of VSMCs through the miR-30a-5p/SMAD1/TGF-ß axis and it may serve as a novel marker of atherogenesis or as a therapeutic target for atherosclerosis.

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Transglutaminase Activities of Blood Coagulant Factor XIII are Dependent on the Activation Pathways and on the Substrates.

A combination of protein substrate disorder and secondary FXIII binding site exposure are utilized to control activity and specificity. From these studies, greater understandings of how FXIII-A targets different substrates are being achieved.

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Reviews&Editorials

Plenty of the editorials are available as full text through the publisher website using the provided link

Ann Oncol

At the crossroad between checkpoint blockade and big data analyses: identification of novel biomarkers and potential targets.

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The end of the second step of the World Health Organization analgesic ladder?

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Blood

A balancing act between toxicity and deep response.

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APL: Nemo finds its sea anemone.

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Donor NK cells facilitate thymopoiesis in allo-BMT.

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Engineered platelets for clinical application: a step closer.

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GVHD prediction based on the microbiome.

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Haematologica

Introduction to the Series on Measurable Residual Disease.

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Measurable residual disease in chronic myeloid leukemia.

In this review we track this development including the international collaboration to standardize results, discuss the integration of molecular monitoring with other factors that affect patients' management, and describe emerging technology. Four case histories describe varying scenarios in which the accurate measurement of residual disease identified patients at risk of disease progression and allowed appropriate investigations and timely clinical intervention.

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Terrific T cells for SARS-CoV-2.

Not available.

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The present and future of measurable residual disease testing in acute myeloid leukemia.

The principles and practices surrounding MRD remain incompletely determined however and the genetic and immunophenotypic heterogeneity of AML may prevent a one-sizefits- al approach. Here, we review the current approaches to MRD testing in AML, discuss strengths and limitations, highlight recent technological advances that may improve such testing, and summarize ongoing initiatives to generate the clinical evidence needed to advance the use of MRD testing in patients with AML.

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Lancet Haematol

CAR T-cell therapies in China: rapid evolution and a bright future.

This strong increase in activity is the result of a culmination of factors in China: strong government support, capital inflow, large patient demand, a unique health-care system, and the efforts of Chinese physicians and scientists. This Series paper provides an overview of the scope of CAR T-cell clinical trials in China (especially in the field of haematological malignancies), analyses the relevant policies, summarises the characteristics of corporate and capital support, and explores the achievements and challenges of CAR T-cell therapy in China to provide a better understanding for further promoting the development of cellular therapy and its clinical application.

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Haematopoietic stem-cell transplantation in China in the era of targeted therapies: current advances, challenges, and future directions.

Despite many challenges in the HSCT setting in China, such as how to redefine the roadmap for HSCT, improve the health-related quality of life of long-term surviving transplant recipients, and promote national and international collaboration, allogeneic HSCT and autologous HSCT will continue to have an important role in treating diverse diseases between now and 2050. The development of HSCT in China will contribute to the worldwide development of HSCT.

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Increasing availability of oral therapy in haematology.

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Regional empowerment through decentralised governance under a centralised regulatory system facilitates the development of cellular therapy in China.

We also highlight several important contributors that could promote innovation and industrialisation of cellular therapy in China. Further efforts are needed to establish a legislative system with clear and cohesive policies for the increasing use of cellular therapy in China, enabling a more prescriptive, diligent, and informed process.

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Miscellaneous

misc publications eg case reports, tools of the trade, images of the month, etc…

Am J Hematol

Diagnostic and therapeutic challenges in mast cell sarcoma.

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Blood

Peripheral agglutination and hemolytic anemia following minor ABO-mismatch hematopoietic progenitor cell transplantation.

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Blood Adv

Ayuk FA, Berger C, Badbaran A, et al. Axicabtagene ciloleucel in vivo expansion and treatment outcome in aggressive B-cell lymphoma in a real-world setting. Blood Adv. 2021;5(11):2523-2527.

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Caplacizumab as frontline therapy in addition to standard treatment in iTTP.

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Clinical and Prognostic Impact of STAG2 Mutations in Myeloid Neoplasms: The Mayo Clinic Experience.

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DOACs in patients with brain cancers, promising but still a long way to go.

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EBV-positive DLBCL frequently harbors somatic mutations associated with clonal hematopoiesis of indeterminate potential.

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Elevated RIPK3 correlates with disease burden in myelofibrosis.

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Loss-of-function lesions impact B-cell development and fitness but are insufficient to drive CLL in mouse models.

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Narkhede M, Goyal G, Shea L, et al. Evaluating real-world treatment patterns and outcomes of mantle cell lymphoma. Blood Adv. 2022; 6(14):4122-4131.

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Wnt inhibitors reduce the unfolded protein response and enhance bortezomib-induced cell death in multiple myeloma.

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Haematologica

Generation of the first monoclonal antibody using mouse hybridomas.

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Images from the Haematologica Atlas of Hematologic Cytology: anaplastic large cell lymphoma, ALK-negative.

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Interleukin-1 receptor associated kinase 1/4 and bromodomain and extra-terminal inhibitions converge on NF-B blockade and display synergistic antitumoral activity in activated B-cell subset of diffuse large B-cell lymphoma with MYD88 L265P mutation.

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Modern real-world patterns of care and clinical outcomes among patients with newly diagnosed diffuse large-B cell lymphoma with or without double/triple-hit status in the United States.

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Structure-function analysis of the role of megakaryoblastic leukemia 1 in megakaryocyte polyploidization.

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Lancet Haematol

Acquired haemophilia in an Edo period Japanese surgical casebook.

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Gene therapy in China: past, present, and future.

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Lenalidomide and risk of second primary malignancy-is disease context key?

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Lower strength stockings: is less better?

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Leukemia

Mutations in spliceosome genes in myelodysplastic neoplasms and their association to ring sideroblasts.

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Sensitive quantitative IgD assay increases progression-free survival prediction accuracy in IgD plasma cell myeloma.

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Letters&Replies

Letters to the editors and authors’ replies

Am J Hematol

Bleeding with concomitant ibrutinib and oral anticoagulant therapy: A population-based cohort study.

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Haematologica

Pirtobrutinib and venetoclax combination overcomes resistance to targeted and CAR Tcell therapy in aggressive mantle cell lymphoma.

Not available.

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Time without transfusion reliance: a novel patient-centric metric for new therapies in myelodysplastic syndromes.

Not available.

Pubmed   Journal   ReadQx 

J Hematol Oncol

Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity.

Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings.

Pubmed   Journal   ReadQx   PMC